Inherited Disorders of the Red Cell Membrane
Hereditary spherocytosis,
transmitted as an autosomal dominant
trait, is the most common inherited disorder of the red cell membrane.
The disorder is a deficiency of membrane proteins (i.e., spectrin and
ankyrin) that leads to gradual loss of the membrane surface during the life
span of the red blood cell, resulting in a tight sphere instead of a concave
disk. Although the spherical cell retains its ability to transport oxygen, it
is poorly deformable and susceptible to destruction as it passes through
the venous sinuses of the splenic circulation. Clinical signs are variable
but typically include mild anemia, splenomegaly, jaundice, and bilirubin
gallstones. A life-threatening aplastic crisis may occur when a sudden
disruption of red cell production (in most cases from a viral infection)
causes a rapid drop in hematocrit and the hemoglobin level. The disorder
usually is treated with splenectomy to reduce red cell destruction.
Hemoglobinopathies
Hemoglobinopathies represent abnormalities in hemoglobin structure that
can lead to accelerated red cell destruction. Two main types of
hemoglobinopathies can cause red cell hemolysis: the abnormal
substitution of an amino acid in the hemoglobin molecule, as in sickle
cell anemia, and the defective synthesis of one of the polypeptide chains
that form the globin
portion of hemoglobin, as in the thalassemias.
Sickle Cell Disease (Anemia).
Sickle cell disease is a chronic disorder resulting in organ failure and
premature death. The disorder affects approximately 50,000 (0.1% to
0.2%) black Americans. Approximately 8% of black Americans carry the
trait. Sickle cell disease results from a point mutation in the β chain of the
hemoglobin molecule, with an abnormal substitution of a single amino
acid, valine, for glutamic acid. Sickle hemoglobin (HbS) is transmitted by
recessive inheritance and can manifest as sickle cell trait (i.e., in
heterozygotes with one HbS gene and one normal HbA gene) or sickle
cell disease (i.e., in homozygotes with two HbS genes). In the
homozygote with sickle cell disease, almost all the hemoglobin is HbS. In
the heterozygote with sickle cell trait, only approximately 40% of the
hemoglobin is HbS. In the homozygote, sickling occurs when the HbS
becomes deoxygenated. The deoxygenated hemoglobin aggregates and
polymerizes, creating a semisolid gel that changes the shape and
deformability of the cell . Sickling of red cells is initially a reversible
process with oxygenation. HbS returns to its normal depolymerized state.
However, with repeated episodes of deoxygenation, the cells remain
permanently sickled. These sickled red cells are abnormally adhesive,
attach to the vessel wall, and cause accumulation of more cells that
obstruct blood flow in the microcirculation, leading to tissue hypoxia.
Sickled cells have a rigid and nondeformable membrane, predisposing to
premature destruction and hemolysis. Thus, the life span of the sickled
cells is markedly reduced. Perhaps the most important factor in
promoting sickling is the amount of HbS and its interaction with other
hemoglobin chains. The person with sickle cell trait who has less HbS has
little tendency to sickle except during severe hypoxia and has virtually no
symptoms. HbF does not interact with HbS or sickle; therefore, infants
with sickle cell disease do not begin to experience the effects of the
sickling until sometime after 4 to 6 months of age, when the HbF has
been replaced by HbS. The factors associated with sickling and
consequent blood vessel occlusion in persons with sickle cell disease
include cold; stress; physical exertion; infection; illnesses that may cause
hypoxia, acidosis, or dehydration; or even such trivial incidents as
reduced oxygen tension induced by sleep. Chronic hemolysis produces
rather severe anemia, .The hyperbilirubinemia that results from the
breakdown products of hemoglobin often leads to jaundice and the
production of pigment stones in the gallbladder. Children with sickle cell
disease may experience growth retardation and susceptibility to
osteomyelitis. Vaso-occlusion accounts for the most severe complications
of sickle cell disease. An acute pain episode results from vessel occlusion
and can affect almost any part of the body. Common sites obstructed by
sickled cells include the abdomen, chest, bones . Acute chest syndrome is
an atypical pneumonia resulting from pulmonary infarction. It affects
approximately 40% of persons with sickle cell disease and is
characterized by fever, chest pain, and cough. The most serious
complication is stroke resulting from cerebral occlusion. The spleen is
especially susceptible to damage by sickle cell hemoglobin predisposes
the person to life-threatening infections by encapsulated organisms such
as Streptococcus pneumoniae, Haemophilus influenzae type b, and
Klebsiella species .Prophylactic penicillin should be begun as early as 2
months of age and continued until at least 5 years of age. Maintaining full
immunization, including administration of H. influenzae and hepatitis B
vaccines, is recommended.